Field of Invention
This invention relates generally to inhibitors of thiol (cysteine) proteases, and most particularly to inhibitors of Cathepsin B (Cat-B).
Proteases are a significant class of enzymes, important in normal physiology but also associated with a number of disease states, including but not limited to inflammation, metastasis, tissue damage following myocardial infarction, bone resorption, and muscle wasting in dystrophic diseases.
Cathepsin B is a cysteine protease involved in normal protein degradation, and as such is generally located in the lysosomes of cells. It is essentially ubiquitous in its tissue distribution. In extracellular or cell-surface forms, Cathepsin B or Cathepsin B-like enzymes have a suggested involvement in several of the above states.
In recent years, investigators have reported a number of synthetic protease inhibitors: Rasnick, in U.S. Pat. No. 4,518,528 (issued May 21, 1985), and in Anal. Biochem. 149, 461-465 (1985), discloses .alpha.-amino fluoromethyl ketones as irreversible inhibitors of serine or cysteine protease; Shaw, et al., in Biochemistry 16, 5857 (1977), Biochem. Biophys. Res. Commun. 89, 1354 (1979), and J. Biol. Chem. 256, 1923 (1981), disclose peptidyl diazomethylketones as irreversible inhibitors of thiol proteases; and Hanada, et al., Agric. Biol. Chem. 42, 529 (1978) and Biochem. J. 201, 189 (1982) disclose epoxysuccinyl peptides as inhibitors of thiol proteases. A limited number of peptidyl acetyloxy-methyl ketones have been reported as enzyme inhibitors: McMurray and Dyckes, in Biochemistry 25, 2298 (1986) disclose an acetyloxymethyl ketone as a reversible inhibitor of the serine protease trypsin, and Larsen and Shaw, in J. Med. Chem. 19, 1284 (1976) disclose acetyloxymethyl ketones as reversible inhibitors of the serine protease chymotrypsin.
A survey of this prior art shows that there is a need for potent and specific thiol protease inhibitors. In particular, there is a need for chemically stable inhibitors that minimize the likelihood of non-specific reactions with plasma or cellular constituents.